Breast Cancer

Biography

Biography: Kim O’Neill

Abstract

Recent clinical trials using chimeric antigen receptors (CAR) T cells have demonstrated tremendous success in eradicating hematologic malignancies targeting CD19. Despite these results, how to translate this success to solid malignancies remains elusive. It is well documented that the vast majority of cancers, particularly the most common such as breast, colon and lung, fail to respond effectively to infusions of CAR T cells. The immunosuppressive tumor microenvironment, the physical barriers of solid malignancies and the unfavorable conditions for T cells at the tumor site make it a difficult challenge for CAR T cells. Moreover, CAR T cells for solid malignancies have also been hampered by expression of the tumor target on normal tissues. Macrophages, the most plastic cells of the haematopoietic system are found in all tissues and show great functional diversity. Two major macrophage phenotypes have been proposed: M1 and M2. M1 macrophages or classically activated macrophages play an important role in the recognition and destruction of cancer cells and are correlated with a more favorable prognosis. Macrophage recruitment to the tumor site is a well-documented event, it has been suggested that in aggressive breast cancer over 50% of the tumor mass is made up of macrophages. Thus, we propose the use of macrophage CARs (MOTO-CARsÔ) as a better approach for the treatment of solid malignancies, particularly breast cancer. Our research takes advantage of the innate ability of macrophages to penetrate tumors and of their tumoricidal abilities. We have genetically engineered the cytosolic signaling domain of the toll-like receptor 4 (TLR-4) and fused it to an extracellular domain single chain variable fragment (scFv) against novel tumor targets discovered in our lab in addition to scFvs against other targets used for CAR therapy. Preliminary results are showing promise and suggest MOTO-CARs may be a major player in driving the success of immunotherapy for breast cancer forward.